Pigment epithelium derived factor (PEDF) is a protein that is expressed in virtually all tissues of the human body, including nerve tissues (Tombran-Tink et al., 1995, J. Neurosci. 15(7 Pt 1):4992-5003). PEDF is an angiogenesis inhibitor with neurotrophic properties and is a member of the second group of the serpin family. (Tombran-Tink and Barnstable, 2003, Nat Rev Neurosci. 4:628-636). PEDF has been shown to have protective effects which extend to neurons of the retina in particular, PEDF prevents damage to rat rod photoreceptors exposed to H2O2 or constant bright light, to rods of the retinal degeneration (rd) and retinal degeneration slow (rds) mutant mice, and to Xenopus rods after RPE detachment. (Cao et al., 1999, J Neurosci Res. 57(6):789-800; Cayouette et al., 1999, Neurobiol Dis. 6(6):523-532; Cao et al., 2001, Invest Opthalmol V is Sci. 42(7):1646-1652; Jablonski et al., 2001, Glia 35(1):14-25). Furthermore, reduced expression of PEDF plays a role in eye pathologies, including retinopathy and macular degeneration (Holekamp et al., 2002, Am J. Opthalmol. 134:220-227). Increased expression of PEDF can induce regression of optical neovascularization (Mori et al., 2002, Invest Opthalmol V is Sci. 43:2428-34). PEDF expression has also been shown to control tumor growth (Wang et al., 2003, Mol. Ther. 2003; 8:72-79; Abe et al., 2004, Am J. Pathol. 164:1225-1232). Thus, PEDF has many therapeutic applications in a variety of pathologies involving angiogenesis and/or neuronal degeneration.
Human PEDF is a 46,312 Da protein, which limits the effectiveness of some forms of delivery for therapeutic applications. The options for alternative delivery systems are limited for large polypeptides such as PEDF. One way in which this problem might be overcome is to identify fragments of PEDF that maintain bioactivity. Identification of functional fragments of PEDF is therefore desirable and structure-function analysis on PEDF has been pursued (Becerra, 1997, Adv Exp Med. Biol. 425:223-37; Bilak et al., 2002, J. Neurosci. 22:9378-9386; Filleur et al., 2005, Cancer Res. 65:5144-5251; Tombran-Tink et al., 2005, J Struc Biol. 151:130-150).
The neuroprotective and antiangiogenic activities of PEDF have been localized to two short adjacent n-terminal fragments of the gene (Li et al., 2006, Exp. Eye. Res. 83:824-33; Gvritishvili et al., 2010, PLoS One. 5:e15056; Bilak et al., 2002, J. Neurosci. 22:9378-86; Mirochnik et al., 2009, Clin. Cancer Res. 15:1655-63).
Given the various potential therapeutic uses of PEDF there is a need in the art for molecules retaining the therapeutic activities of full-length PEDF but which are smaller in size and are easily administrable. The present invention addresses this need.